Circadian and homeostatic contributions to physiology cognition and genome-wide expression in human and mouse variants of the PER3 VNTR polymorphism

PER3 VNTR 多态性的人类和小鼠变体的昼夜节律和稳态对生理认知和全基因组表达的贡献

• 批准号: BB/F022883/1
• 负责人: Derk-Jan Dijk
• 金额: $ 184.32万
• 依托单位: University of Surrey
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF022883%2F1
• 关键词: Circadian; homeostatic; contributions; physiology; cognition

Our sleep-wake cycles are regulated by two clocks / the circadian clock, which has a stable period near 24 h, and a sleep homeostat, which keeps track of how long we have been asleep and awake. It is the interaction between these two clocks that determines whether, at any given time, we feel sleepy or not. Individual variation in these clocks and their interaction also determines whether we are a long or short sleeper, a morning or evening type and whether or not we are very sensitive to the effects of sleep loss on performance. The physiological and molecular mechanisms, as well as the genetic basis for these individual differences in sleep-wake regulation, are not very well known, but the study of 'clock' genes offers real potential for uncovering these mechanisms. PERIOD3, which is one of the clock genes, exists in one longer and one shorter form in humans. This variation is associated with whether you are a morning or evening type. We also showed that this difference has an influence on how much deep sleep we have and how we perform during a night without sleep. It does not affect the timing of the circadian clock. The data suggest that this polymorphism has an influence on the characteristics of our sleep-wake cycles primarily by affecting the sleep homeostat rather than the circadian clock. In the proposed research, we will test the hypothesis that the variation in PERIOD3 influences the sleep homeostat rather than the circadian clock, and also investigate the potential molecular mechanisms by which it affects the characteristics of the sleep and cognition. The research will be conducted in humans and mice. We will study humans carrying different combinations of the longer and the shorter version of the gene, and mice in which their native Period3 gene has been replaced with the two human variants. To characterise the impact of differences in PERIOD3 on either the circadian clock or the sleep homeostat, the sleep-wake cycle will be desynchronised from the circadian clock. This will be accomplished by forcing the sleep-wake cycle to a period much longer than 24 h. The circadian clock cannot keep up with such a long period. Under these circumstances we have separated the biological effects of the circadian clock and the sleep homeostat and we can now test the specific predictions that the PERIOD3 gene affects the homeostatic regulation of sleep and cognitive performance. We will do this by frequent measurements of sleep and performance and a large number of physiological variables. We will also collect blood samples from humans and tissue samples from mice. These samples will be used to assess the circadian variation in expression of >41,000 unique genes and alternative transcripts from human and mouse tissues as well as the circadian variation in the protein encoded by the PERIOD3 gene. The PERIOD3 protein rhythm and the gene expression rhythms will be compared between individuals carrying different variants of the gene. This may provide insights into the molecular mechanism by which the variation of the gene exerts its effects. Tissue samples from humans and mice will also be used to study the period of the circadian clock at the molecular level in cell cultures of these samples. These molecular periods will be compared the period of the clock as measured from the behaviour and hormonal rhythms in the whole organism in an attempt to discover whether variation in PERIOD3 affects this relationship. The proposed research will be conducted by a multidisciplinary team with expertise in sleep and circadian physiology, cognitive psychology, as well as molecular and systems biology. It will contribute to our understanding of the basic mechanisms underlying the daily regulation of sleep duration and timing, cognitive performance and its worsening following sleep loss. This basic knowledge may ultimately be applied to the development of treatments of the many and highly prevalent disorders of sleep-wake cycles.

我们的睡眠-觉醒周期由两个时钟调节：昼夜节律钟，它在24小时左右有一个稳定的周期，睡眠稳态器，它记录我们睡着和醒着的时间。正是这两个时钟之间的相互作用决定了我们在任何给定的时间是否感到困倦。这些生物钟的个体差异及其相互作用也决定了我们是睡眠时间长还是睡眠时间短，是早晨型还是晚上型，以及我们是否对睡眠不足对表现的影响非常敏感。生理和分子机制，以及这些个体差异的睡眠-觉醒调节的遗传基础，是不是很清楚，但“时钟”基因的研究提供了真实的潜力，揭示这些机制。PERIOD 3是生物钟基因之一，在人类中以一种较长和一种较短的形式存在。这种变化与你是早晨型还是晚上型有关。我们还表明，这种差异会影响我们的深度睡眠时间以及我们在不睡觉的夜晚的表现。它不会影响生物钟的时间。这些数据表明，这种多态性主要通过影响睡眠稳态而不是生物钟来影响我们的睡眠-觉醒周期特征。在拟议的研究中，我们将测试PERIOD 3的变化影响睡眠稳态而不是生物钟的假设，并研究其影响睡眠和认知特征的潜在分子机制。这项研究将在人类和小鼠身上进行。我们将研究携带较长和较短版本基因的不同组合的人类，以及用两种人类变体取代其天然Period 3基因的小鼠。为了验证PERIOD 3差异对生物钟或睡眠稳态的影响，将从生物钟中分离睡眠-觉醒周期。这将通过迫使睡眠-觉醒周期超过24小时来实现。生物钟跟不上这么长的时间。在这种情况下，我们已经将生物钟和睡眠稳态的生物学效应分开，现在我们可以测试PERIOD 3基因影响睡眠和认知能力的稳态调节的具体预测。我们将通过频繁测量睡眠和表现以及大量的生理变量来做到这一点。我们还将收集人类的血液样本和小鼠的组织样本。这些样品将用于评估来自人类和小鼠组织的> 41，000个独特基因和替代转录物的表达的昼夜变化以及由PERIOD 3基因编码的蛋白质的昼夜变化。将在携带不同基因变体的个体之间比较PERIOD 3蛋白节律和基因表达节律。这可能为了解基因变异发挥其作用的分子机制提供了线索。来自人类和小鼠的组织样品也将用于在这些样品的细胞培养物中在分子水平上研究生物钟的周期。这些分子周期将与从整个生物体中的行为和激素节律测量的时钟周期进行比较，以试图发现PERIOD 3的变化是否影响这种关系。拟议的研究将由一个多学科团队进行，该团队具有睡眠和昼夜生理学，认知心理学以及分子和系统生物学方面的专业知识。这将有助于我们理解睡眠持续时间和时间的日常调节，认知能力及其在睡眠丧失后的恶化的基本机制。这些基本知识最终可能被应用于开发许多高度流行的睡眠-觉醒周期紊乱的治疗方法。

项目成果

Neuroimaging, cognition, light and circadian rhythms.

• DOI: 10.3389/fnsys.2014.00126
• 发表时间: 2014
• 期刊: Frontiers in systems neuroscience
• 影响因子: 3
• 作者: Gaggioni G;Maquet P;Schmidt C;Dijk DJ;Vandewalle G
• 通讯作者: Vandewalle G

A human sleep homeostasis phenotype in mice expressing a primate-specific PER3 variable-number tandem-repeat coding-region polymorphism.

人的睡眠体内平衡表型在表达灵长类动物特异性PER3的可变串联编码区域多态性的小鼠中。

• DOI: 10.1096/fj.13-240135
• 发表时间: 2014-06
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Hasan S;van der Veen DR;Winsky-Sommerer R;Hogben A;Laing EE;Koentgen F;Dijk DJ;Archer SN
• 通讯作者: Archer SN

Assessment of circadian rhythms in humans: comparison of real-time fibroblast reporter imaging with plasma melatonin.

人类昼夜节律的评估：实时成纤维细胞报告成像与血浆褪黑激素的比较。

• DOI: 10.1096/fj.11-201699
• 发表时间: 2012-06
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Hasan S;Santhi N;Lazar AS;Slak A;Lo J;von Schantz M;Archer SN;Johnston JD;Dijk DJ
• 通讯作者: Dijk DJ

Circadian and Homeostatic Regulation of Human Sleep and Cognitive Performance and Its Modulation by PERIOD3.

• DOI: 10.1016/j.jsmc.2009.02.001
• 发表时间: 2009-06
• 期刊: Sleep medicine clinics
• 影响因子: 2.8
• 作者: Dijk DJ;Archer SN
• 通讯作者: Archer SN